Abstract
A common polymorphism in the cyclin D1 gene enhances the gene's alternate splicing. The alternatively spliced product encodes an altered protein that does not contain sequences involved in the turnover of the protein. We found that hereditary nonpolyposis colorectal carcinoma patients who were homozygous or heterozygous for the mutant allele developed colorectal cancer an average of 11 years earlier than patients who were homozygous for the normal alleles. This is the first report indicating that the cyclin D1 polymorphism influences age of onset of cancer. Because cyclin D1 plays an important role in the G1 to S phase transition of the cell cycle, our findings suggest that cells with the mutant allele accumulate mutations as a result of defective mismatch repair and may also bypass the G1-S checkpoint of the cell cycle more easily than in cells not carrying the polymorphism. The polymorphism has a dominant phenotype.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adult
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Age of Onset
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Aged
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Aged, 80 and over
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Base Pair Mismatch
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Base Sequence
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Carrier Proteins*
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Cell Cycle
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Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
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Colorectal Neoplasms, Hereditary Nonpolyposis / mortality
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Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
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Colorectal Neoplasms, Hereditary Nonpolyposis / physiopathology*
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Cyclin D1 / genetics*
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DNA-Binding Proteins*
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Ethnicity
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Female
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Fungal Proteins / genetics
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Genetic Carrier Screening
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Homozygote
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Humans
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Male
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Middle Aged
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MutL Protein Homolog 1
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MutL Proteins
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MutS Homolog 2 Protein
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Mutation, Missense
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Neoplasm Proteins / genetics
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Nuclear Proteins
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Polymorphism, Genetic*
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Proto-Oncogene Proteins / genetics
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Survival Analysis
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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DNA-Binding Proteins
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Fungal Proteins
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MLH1 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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PMS1 protein, human
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Proto-Oncogene Proteins
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Cyclin D1
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MSH2 protein, human
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MutL Protein Homolog 1
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MutL Proteins
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MutS Homolog 2 Protein